Nanotoxicology is the study of the unknown and potentially unforeseen consequences that may result from nanomaterial exposure due to the unique properties that may cause them to adversely impact living systems. Currently, vast toxicological data gaps exist regarding the risks associated with nanomaterial exposure, and the principal characteristics that may be predictive of nanomaterial interactions with biological systems have yet to be identified due of this lack of information. Thus, rapid testing strategies are immediately necessary to identify the specific features of nanomaterial that result in toxicity in order to mitigate risks from exposure and define structure-property relationships that can be used to predict nanomaterial hazard in lieu of empirical data. The proposed research utilizes an integrative approach to strategically target structure-activity relationships by leveraging nanomaterial characterization and toxicity data using informatics. The goal is to identify the principal features that govern nanomaterial- biological interactions and define key drivers for nanomaterial toxicity. The overall objective of the ONES is to determine the relative influence that size, shape and surface chemistry have on uptake, effects and mechanism of toxicity. Upon completion of the proposed studies, we expect to: i) fill critical information gaps by providing primary data on nanomaterial characterization, fate and biological impact, ii) provide validated assays for rapidly determining nanomaterial characteristics and testing for biological impact, iii) identify the chain of molecular events that lead to a toxic outcome in zebrafish exposed to environmentally relevant nanomaterial concentrations, and iv) deliver an unbiased information platform to delineate which nanomaterial features, or combination of features, modify toxic potential. Such information will have a positive impact and advance the fields of nanomedicine, nanotoxicology, and nanotechnology by reducing the need to empirically test every nanomaterial formulation, providing information on the structural elements that can be modified to minimize inherent nanomaterial toxicity, enhancing community resources for dissemination of important information on nanomaterial, and finally providing new tools for risk assessors to protect humans and the environment from potentially harmful exposures. PUBLIC HEALTH RELEVANCE The proposed studies fill important gaps in our understanding of the human health risk posed by nanomaterial exposure by defining the relationships between nanomaterial physicochemical properties and the biological responses to their exposure. This ONES project will 1) provide hazard data on which to base safety protocols, exposure guidelines, and risk assessments;2) establish design rules to guide the development of high-performance, safe nanomaterial and resulting biomedical technologies;3) establish a predictive platform for nanomaterial hazard identification;and 4) enhance data integration and open-source data sharing on nanomaterial- biological interactions.